Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration

Abstract

PurposeThe relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs.MethodsDogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3–9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3–4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC0–168h after Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression.ResultsThe incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (C max), but not SN38 area under the concentration–time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 C max of 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5–3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses.ConclusionsEP administration avoids both high SN38 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3192-6) contains supplementary material, which is available to authorized users.

Integrated population pharmacokinetics of etirinotecan pegol and its four metabolites in cancer patients with solid tumors

“…The maximum SN38 concentrations resulting from EP administration are lower than those for a 350 mg/m 2 as well as a 60 mg/m 2 irinotecan single dose administration [ 8 ]; the standard dosing regimen for irinotecan is 350 mg/m 2 once every 3 weeks in colon cancer patients. A toxicokinetic study in dogs comparing irinotecan and EP showed that SN38 C max but not AUC was associated with drug-induced neutropenia [ 10 ]. A meta-analysis consisting of 878 patients reported that the association between UGT1A1*28 genotype and irinotecan-induced hematologic toxicity was significant only at higher irinotecan doses that resulted in higher maximum SN38 concentrations [ 23 ].…”

“…EP was designed to provide enhanced anti-tumor efficacy and a favorable tolerability profile through a modulated PK profile that facilitates lower peak plasma levels and sustained exposure of tumor tissue to SN38. In animal models, EP provided increased anti-tumor activity and a better safety profile compared with short-acting Top1 inhibitors [ 9 , 10 ]. EP is a prodrug of irinotecan, consisting of a 20 kDa 4-arm PEG with a single irinotecan molecule conjugated to each arm via a glycine ester; the metabolic pathway of EP is shown in Fig.…”

ATTAIN: Phase III Study of Etirinotecan Pegol Versus Treatment of Physician’s Choice in Patients with Metastatic Breast Cancer and Brain Metastases

“…Through in vivo hydrolysis of the cleavable linker, EP was specifically designed to provide a slow and extended release of irinotecan and subsequently slower transformation to its main active metabolite, SN38 (7-ethyl-10-hydroxycamptothecin), resulting in reduced maximum plasma concentrations (C-max) yet sustained SN38 concentrations [48]. Preclinical and early clinical trials demonstrated an approximate tenfold reduction in the C-max of SN38 after EP administration compared with administration of irinotecan and a prolongation of the SN38 half-life to approximately 50 days, which is in contrast to the half-life of SN38 following conventional administration of irinotecan of ≤2 days [48][49][50][51]. By not overwhelming the capacity of the carboxyl-esterase enzymes that deacetylate irinotecan to SN38, the slow release of irinotecan from EP allows for a more efficient drug activation and resultant greater SN38 area under the concentration time-curve (AUC).…”